Tetrahydro-1,-oxazines

Tetrahydro-1,2-oxazines. Lead tetra-acetate oxidation of isoxazolidine and tetrahydro-l,2-oxazine gives the previously unknown compounds (470) and 

Dipole-moment measurements indicate 62% N-H-axial for tetrahydro-1,3-oxazine and 74% (V-H-axial for 5,5-dimethyltetrahydro-l,3-oxazine,269 but these estimates could well be low. The predominant /V-H-axial conformation is clearly demonstrated by the IR spectrum in the first overtone N-H 

Some of the trends indicated by the 13C-NMR study97 are summarized in Table XX. The conformers were readily recognized by means of y-substituent effects (Section II,B,5). For the simple 3-alkyltetrahydro-l,3-oxazines, the slowing of ring-inversion processes are not detectable by the 13C-NMR variable-temperature technique, and entries 1 and 5 show the axial preference for the 2-methyl and 2-ethyl derivatives with an increased 

Ring-inversion barriers in tetrahydro-l,3-oxazines (Table XXI) decrease with increasing size of substituent. Inclusion of a 4-methyl substituent also decreases A G for the process. 

Dipole-moment measurements were interpreted as favoring the N-alkyl equatorial conformation for a range of N-alkyl tetrahydro-l,3-oxazines, giving 58% eq N-Me, 68% eq N-Et, 86% eq AMPr and 100% eq N-t-Bu,271 but these conclusions can no longer be regarded as reliable. 

13C-NMR-Derived Equilibrium (AGc ) and Kinetic (AGc ) Parameters for Ring Inversion in 

The ring opening of tetrahydro-l,3-oxazines to aldehydes has recently found wide application through the work of Meyers.2-3 2-Alkylidene-tetrahydro-l,3-oxazines, prepared from the readily available 5,6-dihydro-4//-1,3-oxazines, possess strong nucleophilic properties and can react with alkyl halides and carbonyl compounds. The derivatives so obtained can be reduced to tetrahydro-l,3-oxazines, and through ring opening the latter can furnish acyclic, alicyclic, and a,jS-unsaturated aldehydes and their C-l deuterated derivatives.221-223 228 

The first step consists of the formation of lithio salts by treatment of 5,6-dihydrooxazines with phenyl-, n-butyl-, or t-butyllithium in tetra-hydrofuran at -780.1,3,22,223 The lithio salts can readily be alkylated by alkyl halides to 75, and the product can be reduced with aqueous sodium borohydride (or borodeuteride) at pH 7 in tetrahydrofuran-ethanol-water at -35° to -45°C to tetrahydro-l,3-oxazines (76) in quantitative yield. The latter 224-228 23e on hydrolysis with aqueous oxalic acid give aldehydes (77) [Eq. (63)]. 

The lithio salt can react with various electrophiles, as in the reaction of 78 with ketones to yield 79, which after reduction and hydrolysis furnish unsaturated aldehydes (80)225 [Eq. (64)]. 

Further development of the reaction leads to cycloalkanecarboxalde-hydes.222 226 The carbanion (75) can react with a,co-dibromoalkanes, with further base, to obtain the product 81 after reduction and hydrolysis [Eq. (65)]. From 1 mole of the dibromoalkanes and 2 moles of 

The scope of the synthesis was extended by using a 2-vinyloxazine, which led to the formation of propionaldehyde derivatives.227 Another modification of the aldehyde synthesis started with quaternary salts that were treated with sodium hydride, alkylated, then reduced with sodium borohydride to tetrahydro-l,3-oxazines.229 

Meyers et a/.221-222 showed that tetrahydro-l,3-oxazines exist in tautomeric ring-chain forms [Eq. (62)]. When a 5,6-dihydro-1,3-oxazine is reduced to a tetrahydro-1,3-oxazine, some 3-aminoalcohol can also be formed through the reduction of the open-chain imino form [cf. Eq. (62)]. To avoid this the reduction should be carried out with sodium borohydride at -40°C. 

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The formation of 1,3-oxazine derivatives was reported for the first time by Kohn. It consisted in cyclizing 3-aminopropan-l-ol derivatives with aldehydes to yield tetrahydro-1,3-oxazine derivatives (1). 

Aminopropan-l-ol can react with formaldehyde to form the parent tetrahydro-1,3-oxazine (2) itself. With an excess of formaldehyde, a bicyclic compound (3) is obtained. ... 

It was recently shown that the formation of a Schiff s base is the first step of the reaction between 3-aminopropan-l-ol and an aldehyde. The action of acid chlorides, such as tosyl chloride, on the SchifTs base forms the W-acyl derivative of tetrahydro-1,3-oxazine. 

Among various other ways of cyclizing 3-aminopropan-l-ol to a tetrahydro-1,3-oxazine derivative, an interesting reagent is acetylene under pressure ... 

A new method of preparing tetrahydro-1,3-oxazine derivatives (13 and 14) consists in reacting olefins with formaldehyde and ammonium chloride or hydrochlorides of primary amines. ... 

A number of simple reactions are now known which form 2-oxo-tetrahydro-1,3-oxazine (18). Here, also, 3-aminopropanol and some of its derivatives are frequently used, Cyclizing reagents are carbonic acid esters in strongly basic medium, " ethyl chloropropionate, trichloracetic esters, or phenyl isocyanate. An example of the first of these methods is ... 

The thiono derivatives of tetrahydro-1,3-oxazine became a subject matter of some interest since Kjaer and Jensen discovered that products of enzymatic hydrolysis of Malcolma maritima contain 6-methyl- and 6,6-dimethyl-2-thionotetrahydro-l,3-oxazine (26). The authors proved the identity of these compounds with the products of cyclization of 3-hydroxypropyl-isothiocyanate in an alkaline medium. 

Ring opening of some derivatives of tetrahydro-1,3-oxazine can also occur when warmed with aqueous sodium hydroxide ... 

The simple ring opening of tetrahydro-1,3-oxazine derivatives is not the only possible reaction of these heterocyclic compounds catalyzed by mineral acids. An interesting rearrangement of 6-aryl-6-alkyltetrahydro-l,3-oxazines when warmed with concentrated hydrochloric acid was found by Schmiedle and Mansfield ... 

Infrared absorption spectra gave more information regarding the structure of 1,3-oxazine derivatives. These studies were mainly concerned with tetrahydro-ljS-oxazine " and dihydro-1,3-oxazine derivatives. - " According to Eckstein et al. a number of bands of frequencies 1150-1050, 955-925, and 855-800 cm characterize the hemiacetal bond C—0—C. Lukes et expressed the view that a triplet of bands at 1143, 1129, and 1083 cm characterized the tetrahydro-1,3-oxazine ring. However, Bergmann and Kaluszyner assigned these bands to the N—C—O system in the tetrahy dro-1,3-oxazines. 

Other functional groups in tetrahydro-1,3-oxazine derivatives, such as N02, qq so,s7,io5 ]s jj (amincs)and NH (amides) give... 

Drefahl and Horhold discussed the mechanism of N 0 acyl migration in A -benzoyl-l,2-diphenyl-3-aminopropanols. The migration does not seem to be possible in the erythro isomer as it would give an intermediate tetrahydro-1,3-oxazine with a bulky phenyl group in axial position. Consequently the erythro isomer is cyclized with inversion to form 2,5,6-triphenyl-5,6-dihydro-l,3-4 -oxazine... 

Another line of approach to the practical application of 1,3-oxazine derivatives was the suggested use of tetrahydro-1,3-oxazine derivatives as detergents for textile industry, as anticorrosion chemicals, and polymers from 2-oxo derivatives as additives to improve the properties of paper and textiles. ... 

To increase the yields of the ring closure reactions, a new method was developed that was successfully applied for the synthesis of alicyclic fused systems of both the parent oxazolidine-2-thione and tetrahydro-1,3-oxazine-2-thione (85S1149). As an example, the synthesis of 2-thioxoperhydro-l,3-benzoxazine 103 is described. The dithiocarbamate 101, prepared from the amino alcohol 100, carbon disulfide and triethylamine, was treated with ethyl chloroformate in the presence of triethylamine, to give the thioxo derivative 103 via the transition state 102 (85S1149). In this way, the fused-skeleton thioxooxazines (91, X = S, 92) can be prepared with considerably higher yields (50-70%) than by the earlier methods (85S1149). 

Diastereomer Ratios" in the Formation of Tetrahydro-1,3-oxazin-4-ones 133 and 134... 

The conformational analysis of methyl-substituted tetrahydro-1,3-oxazines has been discussed in detail in several contexts (86MRC145,... 

The ring-chain tautomerism of tetrahydro-1,3-oxazines, which involves the reversible addition of a hydroxy group to a C = N bond, is a well-established process and was reviewed recently [94ACH(131)697 95AHC(64)251 96AHC(66)1]. In this context, only the most important characteristics of the ring-chain tautomerism of the alicycle-fused 1,3-oxazines is briefly discussed. 

The tautomerism of the 2-aryl-substituted tetrahydro-1,3-oxazines with the general structures 390, 391, 393, 394, and 396-406 has been studied in detail. Only the structures of the ring forms are shown. In all series, the ring-chain tautomeric equilibria measured in CDCl.i at room temperature can be described by the equation... 

Tetrahydro-1,3-oxazines, Dihydro-1,3-benzoxazines, and Dihydro-3,1-benzoxazines 395... 

The tetrahydro compounds are strongly basic and may be jV-alkylated directly with alkyl halides (64T1173). A number of N-nitroso derivatives have been made by the oxidation of tetrahydro- 1,3-oxazines with peracids (74T3315). Sequential treatment of the oxazine (77) firstly with diketene and then with 4-methyIbenzenesulphonyl azide and triethylamine gives the diazoketone (78), which on irradiation with UV light yields the cepham (79) exclusively (79CC846). 

The main ring syntheses of tetrahydro- 1,3-oxazine derivatives are summarized by diagrams a to d (Fig. 1). Two additional methods comprise the cyclization of six-membered chains, and the hydrogenation or... 

Many papers and patents cover the formation of tetrahydro-1,3-oxazines from 3-aminopropanols and aldehydes or ketones.7-34 Aliphatic, aromatic, or heterocyclic aldehydes introduced the corresponding... 

Numerous tetrahydro- 1,3-oxazines have been prepared by Meyers et al.2-3 by reducing 5,6-dihydro-4//-l, 3-oxazines with sodium borohy-dride. Catalytic hydrogenation of 5,6-dihydrooxazine-6-one failed to produce the tetrahydro derivative, as ring opening occurred.58... 

Additions to the double bond of dihydro-1,3-oxazines can also produce bicyclic derivatives of tetrahydro-1,3-oxazines, such as 959 [Eq. (3)]. Phthaloylglycyl chloride and dihydro-1,3-oxazines in the presence... 

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